Long-Term Outcomes of De-Intensified Chemoradiotherapy for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma

Abstract

To report long-term oncologic outcomes among patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive de-intensified chemoradiotherapy. Major criteria for de-intensification were (1) AJCC 7th edition T0-T3, N0-N2c, M0 (AJCC 8th edition T0-T3, N0-N2, M0), (2) pathologically confirmed p16 positive, and (3) no or minimal/remote smoking history (non-mutated p53 if ≥30 pack-years). Treatment was 60 Gy intensity-modulated radiotherapy with first-choice concurrent cisplatin 30 mg/m2 once per week (alternative regimens permissible for cisplatin ineligible patients). Patients with T0-T2 N0-1 (AJCC 7th edition) were recommended 60 Gy radiation alone. Systemic therapy received included: cisplatin 30 mg/m2 (n = 122), cetuximab (n = 15), cisplatin 40 mg/m2 (n = 12), carboplatin/paclitaxel (n = 2), and radiation alone (n = 25). Kaplan Meier estimates for overall survival (OS), progression-free survival (PFS), locoregional control (LRC), and freedom from distant metastasis (FFDM) were calculated. Cox regression models were used for comparisons among subgroups. A total 176 patients received de-intensified treatment (n = 153 prospective protocol, n = 23 off-protocol). Median follow-up was 52.6 months (range 5.3 - 102.0, 90.8% with minimum 2-year follow-up); 56.8% (n = 100) were never smokers and 43.2% (n = 76) former smokers; former smokers had median 9 pack-years smoking history (range 0.25 - 50) with 46% ≥10 pack-years. Outcomes were as follows: 2-year OS 99.4% and 5-year OS 91.8%; 2-year PFS 94.1% and 5-year PFS 84.3%; 2-year LRC 98.3% and 5-year LRC 95.8%; 2-year FFDM 95.8% and 5-year FFDM 93.2%. Median time to progression events were 21.1 months (range, 7.2 - 54.1) with 37.5% (6 of 16) of recurrences occurring after 24 months. Six total locoregional events occurred (five recurrences and one site of persistent disease), within the 60 Gy planning target volume. Twenty-three patients with T0-T2 N0-1 disease received radiation alone with 2-year PFS 92.9% (5-year 83.8%) and 2-year LRC 100% (5-year 95.2%). Outcomes for former smokers with ≥10 pack-years were comparable to patients with less or no smoking history (2-year PFS 94.1% vs 94.1%; 5-year PFS 90.6% vs 82.7%; HR 0.58, p = 0.38). Early results suggest similar oncologic outcomes among those treated off-protocol (median follow-up 25.6 months) with 1 of 23 patients experiencing locoregional recurrence. Dose de-intensification of 60 Gy radiotherapy with weekly cisplatin results in favorable long-term tumor control in patients with HPV-associated OPSCC. De-intensified 60 Gy alone may be efficacious in carefully selected patients with T0-T2 N0-1 (AJCC 7th edition) disease. Inclusion of biologically favorable patients with more extensive former smoking history in de-intensification clinical trials may be warranted.